Process for preparing prostalglandin derivatives and stereospecific starting material thereof

ABSTRACT

The present invention relates to a process for effectively preparing prostaglandin derivatives and to a stereospecific alkyl halide containing 15S-alcohol group as a starting material.

TECHNICAL FIELD

The present invention relates to a novel process for preparing aprostaglandin derivative of the following formula (1):

-   -   in which    -   R₁ represents H or C₁-C₅-alkyl,    -   X represents CH₂, O, or S, and    -   R′ represents C₂-C₄-alkyl; phenyl optionally substituted by        halogen, C₁-C₅-alkyl, C₁-C₄-alkoxy, CF₃, or C₁-C₃-aliphatic        acylamino; 5- or 6-membered heterocycle containing one or more        hetero atoms selected from a group consisting of nitrogen,        oxygen and sulfur; C₃-C₇-cycloalkyl; or C₃-C₇-cycloalkenyl,    -   a 13,14-dihydro-PGF_(2α) ester derivative, and to an alkyl        halide of the following formula (3a):    -   in which    -   Y′ represents Br or I, and    -   R″ represents a hydroxy-protecting group, preferably        trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,        t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydrofuranyl,        as a starting material.

BACKGROUND ART

Prostaglandin derivative of the above formula (1) is known in Drugs ofthe Future, 1992, 17(8), 691-704; J. Med. Chem., 1993, 36, 243-248, etc.and a process of the following Reaction Scheme 1 published in WO93/00329 can be mentioned as the typical synthesis thereof.

In the above process, ω-chain is introduced into the starting materialof Corey lactone by Wadworth-Emmons method, the ketone group at C15position is reduced to an alcohol group, the remained double bond isreduced again using Pd, α-chain is introduced into a lactol as obtainedthrough some consecutive reactions by Wittig reaction, and the terminalgroup is esterified.

However, the above process has been identified to have the followingproblems.

First, the diastereomeric mixture resulted from the introduction ofω-chain and reduction of the ketone group at C15 position comprises15S-isomer and 15R-isomer in a ratio of 7:3. Therefore,stereoselectivity of the process is not satisfactory. Further, sincethese isomers can hardly be separated, the yield of the desired15S-isomer is as very low as 38%.

Second, the yield of the esterification reaction of the terminalcarboxylic acid after introduction of α-chain by Wittig reaction isreported to be less than 40%. This is the final step of the process, andso the low yield of the final step reaction may exert fatal and seriousinfluence on the total efficacy of the synthesis.

Third, Corey lactone used as a starting material is very expensive,which makes the total process uneconomic.

DISCLOSURE OF INVENTION

Thus, the present inventors have extensively studied to develop aneconomic and effective process for preparing the compound of formula (1)by solving the problems of prior arts as explained above. As a result,we newly designed an alkyl halide containing 15S-alcohol group and thencompleted a process for preparing the compound of formula (1), startingfrom 1,4-addition reaction at the α,β-unsaturated ketone group.According to the process of the present invention, the yield may beincreased by using a stereospecific starting material instead ofreducing the C15 ketone in a poor stereoselective manner; particularly,the low efficacy due to the low yield of esterification reaction of theterminal carboxylic acid may be improved; and there is no more need touse the expensive Corey lactone as a starting material. Therefore, thepresent invention provides an economic and effective synthetic processthat is suitable for a mass production.

Therefore, an object of the present invention is to provide a processfor preparing a prostaglandin derivative of formula (1).

It is another object of the present invention to provide an alkyl halideof formula (3a) as an effective starting material.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention relates to a process for preparing a compound ofthe following formula (1):

-   -   in which    -   R₁ represents H or C₁-C₅-alkyl,    -   X represents CH₂, O, or S, and    -   R′ represents C₂-C₄-alkyl; phenyl optionally substituted by        halogen, C₁-C₅-alkyl, C₁-C₄-alkoxy, CF₃, C₁-C₃-aliphatic        acylamino; 5- or 6-membered heterocycle containing one or more        hetero atoms selected from a group consisting of nitrogen,        oxygen and sulfur;    -   C₃-C₇-cycloalkyl; or C₃-C₇-cycloalkenyl, which comprises the        first step wherein an alkyl halide containing 15S-alcohol of the        following formula (3):    -   in which    -   X and R′ are defined as above,    -   Y represents a leaving group, preferably halogen, and    -   R″ represents a hydroxy-protecting group, preferably        trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,        t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydrofuranyl,        is converted into a cuprate thereof and the cuprate compound is        subjected to a stereoselective 1,4-addition reaction to an        α,β-unsaturated ketone compound of the following formula (2):    -   in which    -   R₁ is defined as above, and    -   R₂ represents a hydroxy-protecting group, preferably        trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,        t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydrofuranyl,        to give a compound of the following formula (4):    -   in which X, R′, R″, R₁ and R₂ are defined as above; the second        step wherein the ketone group on the cyclopentanone ring of the        compound of formula (4) is reduced using a metal hydride to give        an α-alcohol compound of the following formula (5):    -   in which X, R′, R″, R₁ and R₂ are defined as above; and the        third step wherein the alcohol protecting groups on the        cyclopentanone ring and ω-chain in the compound of formula (5)        are removed to give the compound of formula (1).

The process according to the present invention is depicted in thefollowing Reaction Scheme 2 below.

The process of the present invention proceeds through three steps, eachof which is specifically explained in the following.

The First Step: Preparation of the compound of formula (4) from thecompounds of formulae (2) and (3)

The cuprate compound that is formed from the alkyl halide of formula (3)by various methods as explained below is subjected to 1,4-additionreaction to the α,β-unsaturated ketone group of the compound of formula(2) to give the compound of formula (4). Here, the cuprate compound isintroduced into the opposite side to the alkoxy group on thecyclopentenone due to the steric hindrance of the alkoxy group,resulting in a trans configuration with respect to the alkoxy group. Theω-chain thus introduced causes another steric hindrance to the α-chainof the cyclopentenone, whereby the compound of formula (4) in whichα-chain and ω-chain have a trans configuration to each other isobtained.

The cuprate compound can be obtained from the compound of formula (3) byi) adding t-BuLi and then adding one substance selected from a groupconsisting of CuCN, (2-thienyl)Cu(CN)Li and MeCu(CN)Li to the compoundof formula (3); or ii) adding one substance selected from a groupconsisting of CuBr. DMS, CuI and CuBr to a Grignard reagent that isformed from magnesium and the compound of formula (3).

Below, the process for preparing the compound of formula (4) from thealkyl halide of formula (3), where the cuprate compound acts as anintermediate, is specifically explained.

Method {circle around (a)}

To 2 equivalents of the compound of formula (3) dissolved in a solventis added 4 equivalents of t-BuLi at −78° C., which is then stirred. 1equivalent of CuCN is added thereto. The temperature of the reactionsolution is raised to −10° C. to give a lower order-cuprate in ahomogeneous state. This cuprate is cooled again to −78° C. and thenreacted with 0.8-1.0 equivalent of the compound of formula (2).

Method {circle around (b)}

To 1 equivalent of the compound of formula (3) dissolved in a solvent isadded 2 equivalents of t-BuLi at −78° C., which is then stirred. 1equivalent of (2-thienyl)Cu(CN)Li or MeCu(CN)Li is added thereto. Thetemperature of the reaction solution is slowly raised to −40° C. over 30minutes and then lowered again to −78° C. to give a higherorder-cuprate. This cuprate is reacted with 0.8-1.0 equivalent of thecompound of formula (2).

Method {circle around (c)}

To 1 equivalent of the compound of formula (3) dissolved in a solvent isadded 3-4 equivalents of Mg. The Grignard solution thus obtained iscooled to −78° C., and 0.3-1 equivalent of a substance selected from agroup consisting of CuBr.DMS, CuI, and CuBr is added. The reactionmixture is stirred for 1 hour to give Normant reagent. This reagent isreacted with 0.8-1.0 equivalent of the compound of formula (2).

The compound of formula (3) used as a starting material in the above maybe obtained by a process as exemplified in the following Reaction Scheme3.

That is, a nucleophile, preferably carbanion, phenol, thiophenol, oralkaline salt of phenol or thiophenol, is reacted with a chiral epoxidethat can be prepared by a process known in J. Chem. Research(S), 1983,10-11 to open the ring in a stereospecific manner to give an alcoholcompound having S stereochemistry. Particularly, in the case ofcarbanion, the alcohol compound can be obtained by adding 1˜2equivalents of a Grignard reagent and a catalytic amount (0.05˜0.5equivalent) of a substance selected from a group consisting of CuI,CuBr, and CuBr.DMS, stirring for 10 minutes, and slowly adding dropwisean epoxide in a solvent selected from a group consisting ofdiethylether, tetrahydrofuran and dimethylsulfide at reactiontemperatures of −20˜20° C.

Then, the alcohol is protected by a hydroxy-protecting group, preferablytriethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,phenyldimethylsilyl, or tetrahydrofuranyl, and the protecting group ofthe primary alcohol is removed. Particularly, the benzyl group used as aprotecting group can be removed by a catalytic hydrogenation reaction ina solvent selected from a group consisting of methanol and ethanol, andin the presence of palladium as a catalyst; and the paramethoxybenzylgroup can be removed in a solvent mixture of dichloromethane and waterin the presence of DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone)(1.0˜2.0 equivalent) at roomtemperature.

Finally, the primary alcohol is iodinated by I₂, PPh₃, and imidazole ina solvent mixture of acetonitrile and diethylether; or brominated byCBr₄ and PPh₃, or reacting with methane sulfonyl chloride andtriethylamine to give a methanesulfonate, which is then reacted withLiBr in THF solvent.

Particularly, a compound of the following formula (3a) among thecompound of formula (3):

-   -   in which Y′ represents Br or I, and R″ represents a        hydroxy-protecting group, is novel, and thus, it is another        object of the present invention to provide the novel compound of        formula (3a).

The compound of formula (2) can be prepared according to a processdescribed in J. Org. Chem., 1978, 43, 1641-1643, and (2-thienyl)Cu(CN)Lior MeCu(CN)Li can be obtained by adding the commercially available2-thienyl lithium or MeLi to CuCN.

In the above reaction, the solvent dissolving the compounds of formulae(2) and (3) is selected from a group consisting of tetrahydrofuran anddiethylether, and the solvent dissolving t-BuLi is n-pentane. After thecompletion of each reaction, an aqueous solution of NH₄Cl/NH₄OH (9/1) isadded to stop the reaction, Then, the reaction solution is extractedwith diethylether, concentrated, and purified by column chromatography.

The Second Step: Preparation of the compound of formula (5) by Reductionof the compound of formula (4)

The compound of formula (4) obtained by the above 1,4-addition reactionhas a ketone group, which can be reduced by various metal hydrides. Asthe metal hydrides that can be used, those having a heavy sterichindrance, preferably those selected from a group consisting ofsodiumborohydride (NaBH₄), L-selectride, N-selectride and K-selectride,and particularly preferably L-selectride can be mentioned. This isbecause the hydride is apt to attack the cyclopentanone ring from theopposite direction with respect to the alkoxy group in the compound offormula (4) due to the steric hindrance of the alkoxy group, as themetal hydride is bulkier, to selectively give the desired α-alcohol. Thereaction is carried out by adding 1˜3 equivalents of L-selectride to 1equivalent of the compound of formula (4) dissolved in a solvent at −78°C., stirring for 1 to 2 hours, and adding 30% H₂O₂ to stop the reaction.The reaction solution is stirred for 30 minutes at 0° C., extracted withdiethylether, and concentrated to give the compound of formula (5) in astereoselective manner. This compound is used in the next reactionwithout further purification. The solvent used in the above reaction isselected from a group consisting of tetrahydrofuran, diethylether anddichloromethane.

The third step: preparation of the compound of formula (1) throughdeprotection of the compound of formula (5)

The two alcohol protecting groups in the compound of formula (5) can beremoved under an acidic condition, or by using various fluorides (F⁻)particularly when the protecting group is silyl. More specifically, thefollowing methods can be exemplified.

Method Using an Acidic Condition

Method {circle around (a)}

Deprotection is achieved by stirring for 24˜48 hours at room temperaturein the presence of excess NaHSO₄ in a solvent mixture of tetrahydrofuranand water (2:1).

Method Using Fluorides

Deprotection is achieved by

-   -   stirring for 4 hours at 0° C.˜room temperature in the presence        of 2˜4 equivalents of tetrabutylammonium fluoride (Bu₄N⁺F⁻) in a        solvent of tetrahydrofuran (Method {circle around (b)}; or    -   reacting for 3˜4 hours at 0° C. with 2˜10 equivalents of        hydrogen fluoride pyridine (HF-pyridine) in a solvent of        dichloromethane (Method {circle around (c)}; or    -   reacting for 4 hours with fluorosilicic acid (H₂SiF₆) in a        solvent of acetonitrile according to DeShong method (J. Org.        Chem., 1992, 57, 2492) (Method {circle around (d)}).

The present invention will be more specifically explained in thefollowing examples. However, it should be understood that the followingexamples are intended to illustrate the present invention but not in anymanner to limit the scope of the present invention.

EXAMPLE 1 Preparation of the Compound of Formula (3)

Preparation of 1-(4-methoxy-benzyloxy)-5-phenyl-pentan-3-ol

Benzyl magnesium chloride (2.0M in TBF) (64.6 ml, 129.2 mmol) was addedto ThHF (77 ml) and cooled to 0° C. CuI (1.9 g, 9.94 mmol) was added,and the mixture was stirred for 10 minutes.2-[2-(4-Methoxy-benzyloxy)-ethyl]-oxirane (19.5 g, 99.4 mmol) dissolvedin THF (120 ml) was slowly added dropwise thereto. The reaction mixturewas stirred for 1 hour at room temperature and saturated aqueous NH₄Clsolution (100 ml) was added to separate the organic layer. The aqueouslayer was extracted with diethylether (100 ml×2). The organic layerswere combined, washed with saturated aqueous NaCl solution, dried overMgSO₄, filtered, and concentrated to give1-(4-methoxy-benzyloxy)-5-phenyl-pentan-(S)-3-ol (30 g) of a pale yellowoil. This compound was used in the next reaction without furtherpurification.

Preparation of(S)-3-(t-butyldimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenyl Pentane

To DMF (390 ml) were added1-(4-methoxy-benzyloxy)-5-phenyl-pentan-(S)-3-ol (30 g unpurified),imidazole (20.3 g, 298.2 mmol) and TBDMSCI (23 g, 149.8 mmol) in theorder, and the resulting mixture was stirred for 12 hours at roomtemperature. After completion of reaction, the reaction mixture wasdiluted with water (500 ml) and extracted with ethyl acetate (100 ml×3).The organic layers were combined, washed with saturated aqueous NaClsolution, dried over MgSO₄, filtered, and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1)to give (S)-3-(t-butyldimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenylpentane (35 g, Yield of 2 steps 85%) of a colorless and transparent oil.

Preparation of (S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol

(S)-3-(t-butyl dimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenylpentane (15 g, 36.2 mmol) was dissolved in a solvent mixture ofdichloromethane-water (20:1) (252 ml). DDQ (8.2 g, 36.2 mmol) was addedthereto and the mixture was stirred for 30 minutes at room temperature.After completion of the reaction, saturated aqueous NaHCO₃ solution (100ml) was added to the reaction solution to stop the reaction. The organiclayer was separated and the aqueous layer was extracted withdichloromethane. The organic layers were combined, washed with saturatedaqueous NaHCO₃ solution and saturated aqueous NaCl solution, dried overMgSO₄, filtered, and concentrated. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=15:1) to give(S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, Yield 99%)of a yellow oil.

Preparation of (S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenyl pentane

(S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, 36 mmol)was dissolved in dichloromethane (80 ml), triethylamine (12.6 ml, 90.5mmol) was added, and the mixture was cooled to 0° C. Methane sulfonylchloride (4.2 ml, 54.3 mmol) was slowly added dropwise and the resultingmixture was stirred for 12 hours. After completion of the reaction, thereaction mixture was diluted with water (50 ml). The organic layer wasseparated and the aqueous layer was extracted with dichloromethane (50ml×2). The organic layers were combined, washed with saturated aqueousNaCl solution, dried over MgSO₄, filtered, and concentrated. Withoutfurther purification, the residue was dissolved in THF (60 ml). LiBr(7.86 g, 90.5 mmol) was added thereto and the mixture was refluxed for 4hours. After completion of the reaction, water (80 ml) was added to thereaction solution which was then extracted with diethylether. Theorganic layers were combined, washed with saturated aqueous NaClsolution, dried over MgSO₄, filtered, and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1)to give colorless and transparent(S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenyl pentane (11 g. Yield86%).

EXAMPLE 2 Preparation of the Compound of Formula (4) According to Method{circle around (a)}

(S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenyl pentane (8 mmol) wasdissolved in diethylether (17 ml) and cooled to −78° C. t-BuLi(1.7Mpentane solution, 16 mmol) was slowly added dropwise thereto and themixture was stirred for 20 minutes. Then, CuCN (4 mmol) was added andthe temperature of the reaction solution was slowly raised to −10° C. tomake the solution homogeneous. The reaction solution was cooled again to−78° C.7-[(R)-3-(t-butyldimethylsilyloxy)-5-oxo-cyclopent-1-enyl]-hept-5-enoicacid isopropyl ester (3.25 mmol) dissolved in Et₂O (2.5 ml) was slowlyadded dropwise and the mixture was stirred for 2 hours. The temperatureof the reaction solution was raised to −30° C., the reaction was stoppedby the addition of 20 ml of saturated aqueous NH₄Cl solution/28% aqueousNH₄OH solution (9/1), and the reaction solution was warmed to roomtemperature. The reaction solution was diluted with diethylether, washedwith water and brine, dried over Na₂SO₄, filtered, and concentratedunder vacuum. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=20:1) to give11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGE_(2a)isopropyl ester in a yield of 82%.

EXAMPLE 3 Preparation of the Compound of Formula (4) According to Method{circle around (b)}

(S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenyl pentane (3.5 mmol) wasdissolved in diethylether (30 ml) and cooled to −78° C. t-BuLi (1.7Mpentane solution, 7.35 mmol) was added dropwise and the mixture wasstirred for 10 minutes. (2-Thienyl)Cu(CN)Li (0.25M THBF solution, 3mmol) which was newly prepared in another flask was added dropwisethereto. The reaction solution was slowly warmed to −40° C. over 30minutes and then cooled to −78° C. 7-[(R)-3-(t-butyldimethylsilyloxy)-5-oxo-cyclopent-1-enyl]-hept-5-enoic acid isopropyl ester (2.7mmol) dissolved in diethylether (15 ml) was slowly added dropwisethereto. Immediately after the dropwise addition, the reaction vesselwas transferred to a cryostat of −45° C., and then the reaction solutionwas warmed to −30° C. over 30 minutes. After completion of the reaction,the reaction was stopped by adding 10 ml of aqueous NH₄Cl/NH₄OH(9/1)solution. The reaction solution was warmed to room temperature, dilutedwith diethylether, washed with water and brine, dried over Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=20:1) to give11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGE_(2α)isopropyl ester in a yield of 83%.

EXAMPLE 4 Preparation of the Compound of Formula (4) According to Method{circle around (c)}

To a flask containing magnesium turning (25 mmol) was introduced asolution wherein (S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenylpentane (8.3 mmol) and 1,2-dibromoethane (0.05 ml) were dissolved in THF(1.6 ml). The reaction solution was warmed in a thermostat of 70° C. toinitiate formation of Grignard reagent, cooled again to roomtemperature, and stirred for 30 minutes. This solution was diluted withTHF (5 ml), stirred for further 1.25 hour, and cooled to −78° C.CuBr(DMS) (2.0 mmol) dissolved in dimethylsulfide (4 ml) was addeddropwise and the mixture was stirred for 1 hour.7-[(R)-3-(t-butyldimethylsilyloxy)-5-oxo-cyclopent-1-enyl]-hept-5-enoicacid isopropyl ester (6.8 mmol) dissolved in diethylether (7 ml) wasslowly added dropwise thereto and the mixture was stirred for 1 hour.After completion of the reaction, the reaction solution was warmed to−30° C. The reaction was stopped by the addition of 20 ml of aqueousNH₄Cl/NH₄OH(9/1) solution, which was then warmed to room temperature.The reaction solution was diluted with diethylether, washed with waterand brine, dried over Na₂SO₄, filtered, and concentrated under vacuum.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=20:1) to give11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGE_(2α)isopropyl ester in a yield of 77%.

EXAMPLE 5 Preparation of the Compound of Formula (5)

11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGE_(2α)isopropyl ester (3.67 mmol) was dissolved in THF (40 ml), the reactionsolution was cooled to −78° C., and L-selectride (1M THF solution, 7.35mmol) was slowly added dropwise thereto. At this temperature thereaction solution was stirred for 2 hours and the reaction was stoppedby the addition of hydrogen peroxide (30% aqueous solution, 16 mmol).The reaction solution was stirred for 30 minutes at 0° C. and extractedwith diethylether. The organic layers were combined, washed with waterand brine, dried over magnesium sulfate, filtered, and concentratedunder vacuum. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1) to give11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGF_(2α)isopropyl ester in the yield of 90%.

EXAMPLE 6 Preparation of the Compound of Formula (1) According to Method{circle around (a)}

11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGF_(2α)isopropyl ester (40.32 mmol) was dissolved in THF (25 ml), NaHSO₄. H₂O(17.3 mmol) dissolved in water (12.5 ml) was added thereto, and themixture was stirred for 24 hours at room temperature. After completionof the reaction, the reaction solution was extracted with water (20 ml)and CH₂Cl₂ (85 ml). The organic layers were combined, washed withsaturated aqueous NaHCO₃ solution, dried over magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=1:3) to give13,14-dihydro-17-phenyl PGF_(2α) isopropyl ester in a yield of 75%.

EXAMPLE 7 Preparation of the Compound of Formula (1) According to Method{circle around (c)}

11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGF_(2α)isopropyl ester (1.22 mmol) was dissolved in dichloromethane (25 ml),HF. pyr (2.5 ml) was added thereto at 0° C., and the mixture was stirredfor 3 hours. After completion of the reaction, the reaction solution wasdiluted with dichloromethane (10 ml), which was then poured intosaturated aqueous NaHCO₃ solution of 0° C. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over magnesium sulfate, filtered,and concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:3) to give13,14-dihydro-17-phenyl PGF_(2α) isopropyl ester in the yield of 82%.

EXAMPLE 8 Preparation of the Compound of Formula (1) According to Method{circle around (d)}

11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGF_(2α)isopropyl ester (3.6 mmol) was dissolved in acetonitrile (15 ml), H₂SiF₆(4 ml, 25% wt aqueous solution) was added dropwise thereto in an icebath, and the mixture was warmed to room temperature and stirred for 4hours. After completion of the reaction, saturated aqueous NaHCO₃solution was added thereto. The aqueous layer was extracted withdichloromethane. The organic layers were combined, washed with water andbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=1:3) to give 13,14-dihydro-17-phenyl PGF_(2α) isopropyl ester inthe yield of 95%.

INDUSTRIAL APPLICABILITY

In the process of the present invention, a stereospecific startingmaterial is used instead of reducing the ω-chain that may generateundesirable isomers and result in a yield decrease. Further,esterification of the carboxylic acid in the unstable prostaglandincompound in the final step can be avoided, which in turn results in ayield increase in a considerable degree. That is, the total yield of theprocess according to the present invention is 38 to 51% based on theyields of examples above, which is much higher than the maximum yield of15% of the previous process. Moreover, according to the presentinvention, the 15R-isomer resulted from the reduction of ω-chain as animpurity, which can hardly be removed, is not generated, and also theproduction of impurity from the esterification reaction can beprevented. As a result, the prostaglandin derivative of formula (1) canbe easily purified, and so can be synthesized in an economic andeffective manner.

1. A process for preparing a compound of the following formula (1):

in which R₁ represents H or C₁-C₅-alkyl, X represents CH₂, O, or S, andR′ represents C₂-C₄-alkyl; phenyl optionally substituted by halogen,C₁-C₅-alkyl, C₁-C₄-alkoxy, CF₃, C₁-C₃-aliphatic acylamino; 5- or6-membered heterocycle containing one or more hetero atoms selected froma group consisting of nitrogen, oxygen and sulfur; C₃-C₇-cycloalkyl; orC₃-C₇-cycloalkenyl, which comprises the first step wherein an alkylhalide containing 15S-alcohol of the following formula (3):

in which X and R′ are defined as above, Y represents a leaving group,and R″ represents a hydroxy-protecting group, is converted into acuprate thereof and the cuprate compound is subjected to astereoselective 1,4-addition reaction to an α,β-unsaturated ketonecompound of the following formula (2):

in which R₁ is defined as above, and R₂ represents a hydroxy-protectinggroup, to give a compound of the following formula (4):

in which X, R′, R″, R₁ and R₂ are defined as above; the second stepwherein the ketone group on the cyclopentanone ring of the compound offormula (4) is reduced using a metal hydride to give an α-alcoholcompound of the following formula (5):

in which X, R′, R″, R₁ and R₂ are defined as above; and the third stepwherein the alcohol protecting groups on the cyclopentanone ring andω-chain in the compound of formula (5) are removed to give the compoundof formula (1).
 2. The process of claim 1 wherein the compound offormula (3) is converted into its cuprate by i) adding t-BuLi and thenadding one substance selected from a group consisting of CuCN,(2-thienyl)Cu(CN)Li and MeCu(CN)Li to the compound of formula (3); orii) adding one substance selected from a group consisting of CuBr. DMS,CuI and CuBr to a Grignard reagent which is formed from magnesium andthe compound of formula (3).
 3. The process of claim 1 wherein the metalhydride is selected from a group consisting of sodiumborohydride(NaBH₄), L-selectride, N-selectride and K-selectride.
 4. The process ofclaim 1 wherein the alcohol protecting groups are removed in thepresence of H⁺ or F⁻.